The Picornaviridae family includes nearly 70 distinct serotypes of enteroviruses (EVs). Clinical manifestations of enterovirus infection range from mild xe2x80x9csummer coldxe2x80x9d to neurological and cardiovascular disorders.
An enterovirus consists of a simple virus capsid and a single strand of positive sense RNA. The capsid contains four proteins, VP1 to VP4. Variations within capsid proteins VP1 to VP3 are responsible for antigenic diversity among the enteroviruses, with neutralization sites most densely clustered on VP1 (Rueckert, Virology, Lippincott-Raven, New York, 1990, 507). Replication of RNA viruses is directed by viral RNA polymerase of relatively low fidelity that have an error frequency of 10xe2x88x923 to 10xe2x88x924 misincorporated nucleotides per round of replication (Holland et al., Science, 1982, 215:1576-1585; Ward et al., J. Virol., 1988, 62:558-562; and La Torre et al., J. Virol., 1990, 64:664-671). In other words, replication of an enteroviruses genome consisting of about 7500 nucleotides results in a population molecules having on average at least one mutation. Moreover, recombination occurs at a very high frequency in the picornaviruse family (McCahon, Arch. Virol., 1981, 69:1-23).
There is a need to develop compounds which are effective in treating infection by genetically heterogeneous enteroviruses.
One aspect of the present invention relates to a compound having the generic formula: 
Referring to the formula, each of R1 and R3, independently, is C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with one or more halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94C(O)R4, xe2x80x94SR4, xe2x80x94S(O)R4, xe2x80x94S(O)2R4, xe2x80x94NR4R5, xe2x80x94C(O)OR4, xe2x80x94C(O)NR4R5, xe2x80x94NO2, xe2x80x94O(O)CR4, xe2x80x94NR4(O)CR5, xe2x80x94NR4C(O)OR5, xe2x80x94NR4C(O)NR5R6, or R7, provided that if R1 is heteroaryl, the heteroaryl forms a Cxe2x80x94N bond with the imidazolidinone ring. R2 is H, C1-5 alkyl, C1-5 haloalkyl, C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted (e.g., mono- or di-substituted) with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94C(O)R4, xe2x80x94SR4, xe2x80x94S(O)R4, xe2x80x94S(O)2R4, xe2x80x94NR4R5, xe2x80x94C(O)OR4, xe2x80x94C(O)NR4R5, xe2x80x94NO2, xe2x80x94O(O)CR4, xe2x80x94NR4(O)CR5, xe2x80x94NR4C(O)OR5, or xe2x80x94NR4C(O)NR5R6. Each of R4, R5, and R6, independently, is H or C1-4 alkyl. R7 is C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, C1-4 alkyl, C1-4 haloalkyl, xe2x80x94OR4, xe2x80x94NO2, xe2x80x94C(O)OR4, xe2x80x94CN, xe2x80x94NR4R5, or NR4C(O)OR5. T is NH or O; W is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, or xe2x80x94(CH2)4xe2x80x94Oxe2x80x94; m is 4, 5, 6, 7 or 8; and each of x and y, independently, is 0 or 1, provided that at least one of x and y is 1.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine or iodine. The term xe2x80x9calkylxe2x80x9d refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, a C4 alkyl has 4 carbon atoms. The term xe2x80x9chaloalkylxe2x80x9d refers to a straight-chain or branched hydrocarbon chain in which at least one hydrogen is replaced with halogen (e.g., xe2x80x94C(CH3)2CH2Cl or xe2x80x94CF3). The term xe2x80x9carylxe2x80x9d refers to a 6 to 12-carbon monocyclic or multicyclic aromatic system wherein up to 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include but are not limited to phenyl and naphthyl. The term xe2x80x9caralkylxe2x80x9d refers to alkyl substituted with aryl. The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic (each heteroatom being O, N, or S). Examples of heteroaryl groups include but are not limited to pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, quinolinyl, indolyl, and thiazolyl. The aryl or heteroaryl group can be connected to other moieties at one of more ring atoms that are available. For instance, a pyridyl can be connected at its 2-, 3- or 4-position with the 1-N atom of the imidazolidinonyl group.
Referring to the above formula, one subset of the compounds are featured by that each of R1 and R3, independently, is C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7; and R7 is C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2. These compounds include those in which each of R1 and R3, independently, can be pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7, wherein R7 is C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2; those in which R2 can be H, C1-5 alkyl, C1-5 haloalkyl, C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, or xe2x80x94C(O)NR4R5; and those in which x is 1 and T is O.
Another subset of the compounds are featured by that R2 is H, C1-5 alkyl, C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, or xe2x80x94C(O)NR4R5. In these compounds, x can be 1 and T can be O.
A further subset of the compounds are featured by that x is 1 and T is O.
Yet still another subset of the compounds are featured by that y is 1, and W is xe2x80x94(CH2)2xe2x80x94Oxe2x80x94 or xe2x80x94(CH2)3xe2x80x94Oxe2x80x94. These compounds include those in which x is 1 and T is O; those in which each of R1 and R3, independently, is C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7, R7 being C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2; and those in which R2 is H, C1-5 alkyl, C1-5 haloalkyl, C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, or xe2x80x94C(O)NR4R5. They further include compounds in which each of R1 and R3, independently, is pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7, wherein R7 is C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2. Examples of such compounds include: 
Still a further subset of the compounds are featured by that y is 0. These compounds include those in which each of R1 and R3, independently, is C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7, wherein R7 is C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2; those in which R2 is H, C1-5 alkyl, C1-5 haloalkyl, C6-12 aryl, C6-12 aralkyl, or heteroaryl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, or xe2x80x94C(O)NR4R5; those in which x is 1, and T is O. They also include compounds in which each of R1 and R3, independently, is pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, xe2x80x94OR4, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-OR4, xe2x80x94CN, xe2x80x94SR4, xe2x80x94NR4R5, xe2x80x94NR4C(O)NR5R6, or R7, and R7 is C6-12 aryl or heteroaryl, optionally substituted with C1-4 haloalkyl, halogen, xe2x80x94OR4, or xe2x80x94NO2. Examples of such compounds include: 
The compounds described above include their pharmaceutically acceptable salts and prodrugs, if applicable. Such a salt can be formed between a negatively charged ionic group in an imidazolidinone compound (e.g., carbonate) and a positively charged counterion (e.g., sodium, potassium, calcium, or magnesium). Likewise, a positively charged ionic group in an imidazolidinone compound (e.g., ammonium) can also form a salt with a negatively charged counterion (e.g., chloride, bromide, or iodide). Examples of such imidazolidinone salts include the sodium salt of 1-(4-pyridyl)-3-(6-[4-(trifluoromethyl)phenoxy]hexyl)-5-carboxyethyl-2-imidazolidinone and the chloride salt of 1-[7-(4-aminophenoxy)heptyl]-3-(4-pyridyl)-2-imidazolidinone. Examples of prodrugs include esters and other pharmaceutically acceptable compounds, which, upon administration to a subject, are capable of providing imidazolidinone compounds described above.
The compounds of this invention can be used as antiviral agents, particularly against a human enterovirus. Accordingly, another aspect of this invention relates to imidazolidinone compounds as agents against infections of enteroviruses; a method of treating infection by an enterovirus, i.e., administering to a subject in need thereof an effective amount of an imidazolidinone compound described above; and a method of using such an imidazolidinone compound to manufacture a medicament used in treating infection by an enterovirus. The invention also relates to a composition containing an imidazolidinone compound described above and a pharmaceutically acceptable carrier.
The details of many embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the claims.
The imidazolidinones of this invention generally can be prepared by one of the following two methods: (1) N-(2-chloroethyl)urea in the presence of a suitable base gave rise to the imidazolidinone precursor (See Otto Meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, 1998, 423-436) followed by alkylation reaction; and (2) intramolecular cyclization of N-(2-hydroxyethyl) cyanoguanidine by activating its hydroxyl group (See, e.g., Taek Hyeon Kim et al., J. Org. Chem., 1999, 64:2941-2943; and Taek Hyeon Kim et al., Syn. Commun., 1999, 29(16):2753-2758) resulted in the formation of a 4-substituted cyanoguanidine intermediate which was then applied to alkylation reactions. Shown below are two schemes which respectively depict these two different methods. In both schemes, R1, R2, R3, m, T, and x are as defined above; and n is 1-4. 
In Scheme 2, one of the common starting materials, i.e., S-methyl-N-cyano-Nxe2x80x2-pyridylisothiourea (V), can be readily prepared by coupling 4-amino pyridine with dimethyl N-cyanodithioiminocarbonate according to well-known methods. See, e.g., Charlotte Schou et al., Bioorganic and Medicinal Chemistry Letters, 1997, 7(24):3095-3100.
Other imidazolidinone compounds of this invention (e.g., referring to the generic formula, those in which y is 0) can also be synthesized by either of the two methods described above, by using a suitable alkylating agent, e.g., Brxe2x80x94(CH2)mxe2x80x94(T)xxe2x80x94R3.
An imidazolidone compound thus prepared can be preliminarily screened by an in vitro inhibition assay (e.g., plaque reduction assay) for its activity against viruses, and particularly, enteroviruses. A compound that demonstrates high activity in the preliminary screening can be further evaluated by in vivo methods well known in the art (see, e.g., Daniel C. Pevear et al., Antimicrobial Agents and Chemotherapy, 1999, 43(9): 2109-2115).
A suitable imidazolidinone compound, its salt, or its prodrug in an effective amount is formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before it is administered to a subject in need of an antivirus treatment. xe2x80x9cAn effective amountxe2x80x9d refers to the amount of the compound which is required to confer therapeutic effect on the treated subject. The effective amount varies, as recognized by those skilled in the art, depending on factors such as the route of administration, the excipient usage, the distance of tumor from the skin surface, the source of the irradiation, and the optional co-usage with other therapeutic treatments including use of other anti-tumor compounds. Examples of pharmaceutically acceptable carriers include water, colloidal silica oxide, magnesium sterate, lipid, lipoprotein, blood protein, and cellulose.
The pharmaceutical composition may be administered via a parenteral route, e.g., topically, intraperitoneally, and intravenously. Examples of parenteral dosage forms include an active compound dissolved in phosphate buffered saline (PBS), or admixed with any other pharmaceutically acceptable carrier. Solubilizing agents, such as cyclodextrins, or other solubilizing agents well known to those familiar with the art, can also be included in the pharmaceutical composition.
Without further elaboration, it is believed that one skilled in the art, based on the description herein, can utilize the present invention to its fullest extent. The following specific examples, which described synthesis and biological testing of imidazolidinone compounds, are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.